The continued long-term goal of this Program is to examine signals and signal transduction mechanisms in the gastrointestinal (Gl) tract and to provide useful new information on these mechanisms by which gastrointestinal hormones (GIH) and growth factors influence gut function. Most of these mechanisms overlap and there are clear parallels in the mechanisms addressed by each project. The specific aims of the projects in this proposal are logical extensions of our previous findings. In Project 1, we will examine the central hypothesis that aging results in tissue-specific alterations of proliferation in the pancreas. We will examine the mechanisms by which the PI3K/Akt signaling pathway and alterations in IGF-I expression contribute to age-related changes in cell responsiveness. In Project 2, we will continue our studies on the signal mechanisms that regulate intestinal cholecystokinin (CCK) secretion by studies on the recently discovered peptide, apelin. These findings will be important in the development of novel strategies for the treatment of digestive diseases and appetite disorders. In Project 3, we will examine a novel role for mitogen-activated protein kinases (MAPKs) in the regulation of GIH-mediated signals for Ca2+ mobilization and cross-talk between bombesin and epidermal growth factor signal transduction pathways. In Project 4, we will examine mechanisms of interactions between transforming growth factor-beta (TGF-beta) and GIH leading to regulation of gene expression and cellular processes in the gut. In Project 5, we will study the actions of PTHrP on the PI3K/Akt signal transduction pathway, its regulation of integrin expression and function, to provide new insight into the mechanisms of invasion and metastasis of colon cancer cells that should allow us to identify novel therapeutic targets. In this Program Project, our studies will examine signaling mechanisms in whole animals, cellular, subcellular and molecular models to define and understand signaling mechanisms of GIH to meet the long-term objectives of our program. The increased investigative depth exhibited in this current proposal, the unifying hypothesis for the program as a whole, the sharp focus of the specific aims and synergistic cohesion among the various projects are important strengths of the proposal. We have addressed the concerns raised in the summary statement of our prior application, and we have continued to demonstrate the productivity of our collaborating efforts.